Alveolar epithelium is comprised of two distinct cell populations: type II (AT2) and type I (AT1) cells. AT2 cells serve as facultative progenitors for maintenance and repair of alveolar epithelium, while AT1 cells have been viewed as terminally differentiated. Wnt/?-catenin signaling plays dichotomous roles in lung development, directing progenitor maintenance/expansion vs differentiation. Mechanisms that specify each of these roles in any cellular or tissue context (including the lung), and in particular the roles of Wnt/?-catenin-dependent signaling in lung repair and adult alveolar epithelial cell (AEC) differentiation are largely unknown. Our recent development of novel inhibitors that differentially modulate interactions between b-catenin and either of its transcriptional coactivators, p300 or CREB binding protein (CBP), have led us to propose a model to explain dichotomous activities of Wnt/?-catenin signaling, in which CBP/?-catenin-mediated transcription is critical for progenitor cell maintenance while p300/?-catenin-mediated transcription is critical for initiation of differentiation and decreased cellular potency. The overall goal of this proposal is to investigate the role of Wnt/?-catenin signaling, and especially differential interactions of ?-catenin with CBP and p300, in directing AEC differentiation and phenotypic transitions in normal and injured adult lung. ?-catenin/p300 interactions are modulated by p300 phosphorylation, while the transcription factor GATA-6 (which promotes AT1 cell phenotype) controls the balance between progenitor maintenance vs differentiation during development/regeneration through interactions with Wnt signaling. We hypothesize that, in normal and injured adult lung, (1) ?-catenin/p300-dependent signaling plays a critical regulatory role in AT1 cell differentiation, (2) p300 phosphorylation modulates b-catenin/p300 interactions to promote AT1 cell phenotype, and (3) regulation of AT1 cell phenotype involves interactions between Wnt5a and GATA-6. We will use our well-characterized models of AEC differentiation in vitro and our expertise in characterizing AEC differentiation and genetically modified mice, in conjunction with our novel inhibitors, to differentially regulate coactivator/?-catenin interactions in order to address the following Specifc Aims: 1) Investigate the role of differential coactivator/b-catenin interactions during adult AEC differentiation in vitro; 2) Characterize mechanisms underlying differential coactivator/?-catenin interactions during adult AEC transdifferentiation; and 3) Explore differential coactivator/?-catenin interactions in adult AEC transdifferentiation in vivo. Elucidating mechanisms underlying the role of this developmentally relevant Wnt signaling pathway in promoting normal epithelial cell differentiation is critically important to understanding mechanisms of repair following lung injury. Availability of unique small molecule inhibitors that promote normal AEC differentiation (and that are currently being evaluated in clinical trials) additionally offers the possibility of apid translation of these findings to improve outcome by enhancing epithelial repair.